DESCRIPTION: This is the first submission of an application that proposes to investigate the role of Pgp gene expression in the development of hepatocarcinogenesis (HCC) in rodent cells. Previous studies have shown that mdr1a and mdr1b expression is consistently elevated in HCC in mouse and rat, respectively. This increased expression is observed in HCC arising from both viral and carcinogenic insults, leading the applicant to suggest that multiple carcinogenic pathways "converge" in the development of HCC, with Pgp gene activation as one of the end-points of this convergence. Therefore, he suggests that analysis of Pgp gene activation will provide important insights into the pathogenic pathways in the various carcinogenic programs and identify the cellular origins of HCC. Moreover, he states that the observation that different isoforms of Pgp are activated in rat versus mouse indicates that the isoforms can compensate for each other. He now proposes to 1) continue the analysis of a cell-specific enhancer element that has been identified within the mdr1b promoter; 2) develop an effective delivery system for targeting recombinant DNA into HCC and 3) investigate the role of MDR in the pathogenesis of liver cancer.